US7727953B2 - Crystalline form of a drug - Google Patents

Crystalline form of a drug Download PDF

Info

Publication number
US7727953B2
US7727953B2 US11/615,234 US61523406A US7727953B2 US 7727953 B2 US7727953 B2 US 7727953B2 US 61523406 A US61523406 A US 61523406A US 7727953 B2 US7727953 B2 US 7727953B2
Authority
US
United States
Prior art keywords
acxgvi
tnirpnhch
crystalline form
oil
term
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US11/615,234
Other versions
US20070185034A1 (en
Inventor
John C. Tolle
Ahmad Y. Sheikh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Inc
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to US11/615,234 priority Critical patent/US7727953B2/en
Assigned to ABBOTT LABORATORIES reassignment ABBOTT LABORATORIES ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SHEIKH, AHMAD Y, TOLLE, JOHN C.
Publication of US20070185034A1 publication Critical patent/US20070185034A1/en
Application granted granted Critical
Publication of US7727953B2 publication Critical patent/US7727953B2/en
Assigned to ABBVIE INC. reassignment ABBVIE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ABBOTT LABORATORIES
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention pertains to a crystalline form of Ac-Sar-Gly-Val-D-allo-Ile-Thr-Nva-Ile-Arg- ProNHCH 2 CH 3 , ways to make it, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it.
  • the acetic acid salt of Ac-Sar-Gly-Val-D-allo-Ile-Thr-Nva-Ile-Arg-ProNHCH 2 CH 3 .CH 3 CO 2 H (AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H) is useful for treating diseases that are caused or exacerbated by angiogenesis.
  • crystallinity of this compound may effect, among other physical and mechanical properties, its solubility, dissolution rate, hardness, compressability and melting point, there is an existing need in the process and therapeutic arts for identification of crystalline forms of AcXGVI*TNIRPNHEt.CH 3 CO 2 H and ways of reproducibly making it.
  • FIG. 1 shows a powder diffraction pattern of AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1.
  • One embodiment of this invention pertains to AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1 characterized, when measured at about 25° C. with Cu-K ⁇ radiation, by a powder diffraction pattern with at least three peaks having respective 2 ⁇ values of about 2.6, 4.7, 5.2, 5.5, 7.2, 8.9, 11.6, 13.6 or 14.4.
  • Another embodiment pertains to AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1 having substantial crystalline purity and characterized, when measured at about 25° C. with Cu-K ⁇ radiation, by a powder diffraction pattern with at least three peaks having respective 2 ⁇ values of about 2.6, 4.7, 5.2, 5.5, 7.2, 8.9, 11.6, 13.6 or 14.4.
  • Still another embodiment pertains to AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1 having substantial crystalline purity and substantial chemical purity and characterized, when measured at about 25° C. with Cu-K ⁇ radiation, by a powder diffraction pattern with at least three peaks having respective 2 ⁇ values of about 2.6, 4.7, 5.2, 5.5, 7.2, 8.9, 11.6, 13.6 or 14.4.
  • compositions comprising an excipient and AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1.
  • Still another embodiment pertains to methods of treating diseases that are caused or exascerbated by angiogenesis in a mammal comprising administering thereto a therapeutically effective amount of a composition comprising or made from AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1.
  • This invention pertains to discovery of AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1, ways to characterize it, compositions containing it and methods of treating diseases caused or exascerbated by angiogenesis using it.
  • Gly or the symbol “G,” as used herein, means glyclyl.
  • D-allo-Ile or the symbol “I*,” as used herein, means D-allo-isolucinyl.
  • Thr or the symbol “T,” as used herein, means threoninyl.
  • Arg or the symbol “R,” as used herein, means arginyl.
  • diseases caused or exascerbated by angiogenesis means angiogenic diseases (e.g. diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, infantile hemangiomas, cancer (lung, breast, stomach, bladder, colon, pancreatic, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), glioblastoma, infantile hemangioma)) (Lab. Investig. (1992), 67(4), 519-528; Anat. Rec. (1997), 249(1), 63-73; Int.
  • diseases e.g. diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, infantile hemangiomas, cancer (lung, breast, stomach, bladder, colon, pancreatic, ovarian, prostate and rectal cancer and hema
  • amorphous means a supercooled liquid substance or a viscous liquid which may appear as a solid but is not crystalline. Amorphous substances do not have a melting point but soften or flow above a certain temperature known as the glass transition temperature.
  • crystalline means having a regularly repeating arrangement of molecules which is maintained over a long range or external face planes.
  • substantially crystalline purity means at least about 95% crystalline purity, preferably about 97% crystalline purity, more preferably about 99% crystalline purity, and most preferably about 100% crystalline purity.
  • crystalline purity means percentage of a particular crystalline form of a compound in a sample which may contain amorphous form of the compound, one or more than one other crystalline forms of the compound other than the crystalline form of the compound of this invention, or a mixture thereof.
  • substantially chemical purity means about 95% chemical purity, preferably about 97% chemical purity, more preferably about 98% chemical purity, and most preferably about 100% chemical purity.
  • chemical purity means percentage of a particular compound in a sample.
  • seed crystal means a particular crystalline form of a substance having mass. It is meant to be understood that such a crystal may be small enough to be airborne or invisible to the eye without means of detection.
  • a therapeutically acceptable amount of AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1 depends on recipient of treatment, disorder being treated and severity thereof, composition containing it, time of administration, route of administration, duration of treatment, its potency, its rate of clearance and whether or not another drug is co-administered.
  • the amount of AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1 used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight.
  • Single dose compositions contain these amounts or a combination of submultiples thereof.
  • AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1 may be administered with or without an excipient.
  • Excipients include but are not limited to, for example, encapsulating materials and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising and made with AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1 to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphat
  • CH 3 CO 2 H Crystalline Form 1 to be administered ophthalmically or orally in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising and made with AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1 to be administered osmotically include, for example, chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising and made with AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1 to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising and made with AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1 to be administered rectally or vaginally include, but are not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like.
  • the mixture was monitored for the consumption of Ac-Sar-Gly-Val-D-allo-Ile-Thr-OH by HPLC, warmed to 20° C., treated with water (50 Kg/Kg of Ac-Sar-Gly-Val-D-allo-Ile-Thr-OH) while maintaining a temperature of 35° C., mstirred for 1 hour, adjusted to 20° C., adjusted to pH 5.4 ⁇ 0.6 with 1N sodium hydroxide or acetic acid, as needed and further diluted with water to provide a solution that contains about 5 g of EXAMPLE 1/Kg. This solution was suitable for reverse osmosis.
  • EXAMPLE 1 (3.44 Kg) was purified with a Nanomax 50 membrane cartridge in a NIRO reverse osmosis unit at 175 ⁇ 50 psi and a 20-30° C. The solution was diafiltered with distilled water (850 Kg/Kg) and concentrated 4 ⁇ to provide a solution with about 20 g EXAMPLE 1/Kg of solution. This solution was diafiltered with 1% sodium acetate (pH 5.2 ⁇ 0.5, 930 Kg/Kg of EXAMPLE 1). The permeate solution was monitored for chloride by ion selective electrode until the salt exchange (chloride to acetate) was complete. The retentate was monitored for the removal of HOBt by HPLC until the process was complete.
  • the product solution was diafiltered with 20 ppm acetic acid solution (870 Kg/Kg of EXAMPLE 1).
  • the permeate solution was monitored by conductance for sodium acetate until the sodium acetate removal was complete.
  • the retentate was monitored by HPLC for the removal of EDU until complete.
  • the product solution was concentrated to about 80 g EXAMPLE 1/Kg of solution, drained to a container and washed twice with distilled water (4-5 Kg/Kg EXAMPLE 1). The rinses are combined with the product solution.
  • the yield of AcXGVI*TNIRPNHCH 2 CH 3 was about 90-97%.
  • the product solution of EXAMPLE 2 (1 Kg, about 42 g AcXGVI*TNIRPNHCH 2 CH 3 /Kg solution) was double filtered (0.45 and 0.2 ⁇ m filters in series) into a reactor.
  • the solution was distilled under vacuum at 50° C. to approximately 15 L.
  • the solution was warmed to 40° C., treated with isopropanol (4 Kg/Kg AcXGVI*TNIRPNHCH 2 CH 3 ) to provide a ratio of AcXGVI*TNIRPNHCH 2 CH 3 (Kg)/water(L)/isopropanol(L) of 1:4:15.
  • Filtered isopropyl acetate (16 Kg/Kg AcXGVI*TNIRPNHCH 2 CH 3 ) was added, and the mixture was cooled to 25° C. Additional filtered isopropyl acetate (39 Kg/Kg AcXGVI*TNIRPNHCH 2 CH 3 ) was added at a rate of 6-9 Kg/h), and the mixture was stirred for 3 hours and filtered.
  • the filtrate was washed with a mixture of isopropanol (3 Kg/Kg AcXGVI*TNIRPNHCH 2 CH 3 ) and isopropyl acetate (14 Kg/Kg AcXGVI*TNIRPNHCH 2 CH 3 ).
  • the solids were dried under vacuum at 45° C. for 12 hours, de-lumped with a mortar and pestle and screened through Nos. 10 and 18 sieves.
  • the solids may be hydrated by transferral to a dryer containing a pan of water. The dryer was held at 40° C. for 8-24 hours under vacuum and further dried under vacuum at 45° C. regardless of the optional moisture treatment.
  • the drying was monitored by GC for the removal of isopropanol and isopropyl acetate until complete.
  • the yield of AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H was 86-94%.
  • a sample of AcXGVI*TNIRPNHCH 2 CH 3 .CH 3 CO 2 H Crystalline Form 1 for powder diffraction analysis was applied as a thin layer, with no prior grinding, to the analysis well of a Scintag ⁇ 2 Diffraction Pattern System having the following parameters: x-ray source: Cu-K ⁇ ; range: 2.00°-40.00° 2 ⁇ ; scan rate: 1.00 degree per minute; step size: 0.02°; temperature: about 25° C.; wavelength: 1.54178 ⁇ (Cu-K ⁇ ).
  • peak heights may vary and will be dependent on variables such as the temperature, size of crystal size or morphology, sample preparation, or sample height in the analysis well of the Scintag ⁇ 2 Diffraction Pattern System.
  • peak positions may vary when measured with different radiation sources.
  • Cu-K ⁇ 1 , Mo-K ⁇ , Co-K ⁇ and Fe-K ⁇ radiation having wavelengths of 1.54060 ⁇ , 0.7107 ⁇ , 1.7902 ⁇ and 1.9373 ⁇ , respectively, may provide peak positions that differ from those measured with Cu-K ⁇ radiation.
  • the phrase about 2.6, 4.7, 5.2, 5.5, 7.2, 8.9, 11.6, 13.6 or 14.4 means about 2.6, about 4.7, about 5.2, about 5.5, about 7.2, about 8.9, about 11.6, about 13.6 or about 14.4 or 2.6 ⁇ 0.1°, 4.7 ⁇ 0.1°, 5.2 ⁇ 0.1°, 5.5 ⁇ 0.1°, 7.2 ⁇ 0.1°, 8.9 ⁇ 0.1°, 11.6 ⁇ 0.1°, 13.6 ⁇ 0.1°or 14.4 ⁇ 0.1°.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Ac-Sar-Gly-Val-D-allo-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3 Crystalline Form 1, ways to make it, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed.

Description

This application claims priority to U.S. Provisional Parent Application Ser. No. 60/754,743, filed Dec. 29, 2005.
FIELD OF THE INVENTION
This invention pertains to a crystalline form of Ac-Sar-Gly-Val-D-allo-Ile-Thr-Nva-Ile-Arg- ProNHCH2CH3, ways to make it, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it.
BACKGROUND OF THE INVENTION
The acetic acid salt of Ac-Sar-Gly-Val-D-allo-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3.CH3CO2H (AcXGVI*TNIRPNHCH2CH3.CH3CO2H) is useful for treating diseases that are caused or exacerbated by angiogenesis.
Because the crystallinity of this compound may effect, among other physical and mechanical properties, its solubility, dissolution rate, hardness, compressability and melting point, there is an existing need in the process and therapeutic arts for identification of crystalline forms of AcXGVI*TNIRPNHEt.CH3CO2H and ways of reproducibly making it.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 shows a powder diffraction pattern of AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1.
 SUMMARY OF THE INVENTION
One embodiment of this invention, therefore, pertains to AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 characterized, when measured at about 25° C. with Cu-Kα radiation, by a powder diffraction pattern with at least three peaks having respective 2θ values of about 2.6, 4.7, 5.2, 5.5, 7.2, 8.9, 11.6, 13.6 or 14.4.
Another embodiment pertains to AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 having substantial crystalline purity and characterized, when measured at about 25° C. with Cu-Kα radiation, by a powder diffraction pattern with at least three peaks having respective 2θ values of about 2.6, 4.7, 5.2, 5.5, 7.2, 8.9, 11.6, 13.6 or 14.4.
Still another embodiment pertains to AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 having substantial crystalline purity and substantial chemical purity and characterized, when measured at about 25° C. with Cu-Kα radiation, by a powder diffraction pattern with at least three peaks having respective 2θ values of about 2.6, 4.7, 5.2, 5.5, 7.2, 8.9, 11.6, 13.6 or 14.4.
Still another embodiment pertains to compositions comprising an excipient and AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1.
Still another embodiment pertains to methods of treating diseases that are caused or exascerbated by angiogenesis in a mammal comprising administering thereto a therapeutically effective amount of a composition comprising or made from AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1.
DETAILED DESCRIPTION OF THE INVENTION
This invention pertains to discovery of AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1, ways to characterize it, compositions containing it and methods of treating diseases caused or exascerbated by angiogenesis using it.
The term “Ac,” as used herein, means acetyl.
The term “Sar,” or the symbol “X,” as used herein, means sarcosyl.
The term “Gly,” or the symbol “G,” as used herein, means glyclyl.
The term “Val,” or the symbol “V,” as used herein, means valyl.
The term “D-allo-Ile,” or the symbol “I*,” as used herein, means D-allo-isolucinyl.
The term “Thr,” or the symbol “T,” as used herein, means threoninyl.
The term “Nva,” or the symbol “N,” as used herein, means norvalyl.
The term “Ile,” or the symbol “I,” as used herein, means isolucinyl.
The term “Arg,” or the symbol “R,” as used herein, means arginyl.
The term “Pro,” or the symbol “P,” as used herein, means prolinyl.
The term “diseases caused or exascerbated by angiogenesis,” as used herein, means angiogenic diseases (e.g. diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, infantile hemangiomas, cancer (lung, breast, stomach, bladder, colon, pancreatic, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), glioblastoma, infantile hemangioma)) (Lab. Investig. (1992), 67(4), 519-528; Anat. Rec. (1997), 249(1), 63-73; Int. J.Cancer (1995), 63(5), 694-701; Vasc. Biol. (1995), 15(11), 1857-6)), pulmonary hypertension in patients with thromboembolic disease (J. Thorac. Cardiovasc. Surg. 2001, 122 (1), 65-73), and autoimmune diseases (psoriasis, kidney rejection, graft versus host disease).
The term “amorphous,” as used herein, means a supercooled liquid substance or a viscous liquid which may appear as a solid but is not crystalline. Amorphous substances do not have a melting point but soften or flow above a certain temperature known as the glass transition temperature.
The term “crystalline,” as used herein, means having a regularly repeating arrangement of molecules which is maintained over a long range or external face planes.
Unless stated otherwise, percentages herein are weight/weight (w/w) percentages.
The term “substantial crystalline purity,” as used herein, means at least about 95% crystalline purity, preferably about 97% crystalline purity, more preferably about 99% crystalline purity, and most preferably about 100% crystalline purity.
The term “crystalline purity,” as used herein, means percentage of a particular crystalline form of a compound in a sample which may contain amorphous form of the compound, one or more than one other crystalline forms of the compound other than the crystalline form of the compound of this invention, or a mixture thereof.
The term “substantial chemical purity,” as used herein, means about 95% chemical purity, preferably about 97% chemical purity, more preferably about 98% chemical purity, and most preferably about 100% chemical purity.
The term “chemical purity,” as used herein, means percentage of a particular compound in a sample.
The term “seed crystal,” as used herein, means a particular crystalline form of a substance having mass. It is meant to be understood that such a crystal may be small enough to be airborne or invisible to the eye without means of detection.
A therapeutically acceptable amount of AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 depends on recipient of treatment, disorder being treated and severity thereof, composition containing it, time of administration, route of administration, duration of treatment, its potency, its rate of clearance and whether or not another drug is co-administered. The amount of AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight. Single dose compositions contain these amounts or a combination of submultiples thereof.
AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 may be administered with or without an excipient. Excipients include but are not limited to, for example, encapsulating materials and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.
Excipients for preparation of compositions comprising and made with AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, mixtures thereof and the like. Excipients for preparation of compositions comprising and made with AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 to be administered ophthalmically or orally in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like. Excipients for preparation of compositions comprising and made with AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 to be administered osmotically include, for example, chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like. Excipients for preparation of compositions comprising and made with AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water, mixtures thereof and the like. Excipients for preparation of compositions comprising and made with AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 to be administered rectally or vaginally include, but are not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like.
The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention.
EXAMPLE 1
Ac-Sar-Gly-Val-D-allo-Ile-Thr-OH (2.14 Kg, 3.56 mol), Ile-Arg-ProNHEt dihydrochloride salt (1.00-1.06 equivalents) and 1-hydroxybenzotriazole (1.3 equivalents) were dissolved in dimethylformamide (14 Kg/Kg Ac-Sar-Gly-Val-D-allo-Ile-Thr-OH) at 28° C. The solution was cooled to −10° C. and treated with 2,4,6-collidine (2.1 mole equivalents) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC.HCl, 1.1-1.2 equivalents) in distilled water (1 Kg/Kg EDAC.HCl) while maintaining the temperature at −5° C. The mixture was monitored for the consumption of Ac-Sar-Gly-Val-D-allo-Ile-Thr-OH by HPLC, warmed to 20° C., treated with water (50 Kg/Kg of Ac-Sar-Gly-Val-D-allo-Ile-Thr-OH) while maintaining a temperature of 35° C., mstirred for 1 hour, adjusted to 20° C., adjusted to pH 5.4±0.6 with 1N sodium hydroxide or acetic acid, as needed and further diluted with water to provide a solution that contains about 5 g of EXAMPLE 1/Kg. This solution was suitable for reverse osmosis.
EXAMPLE 2
The solution of EXAMPLE 1 (3.44 Kg) was purified with a Nanomax 50 membrane cartridge in a NIRO reverse osmosis unit at 175±50 psi and a 20-30° C. The solution was diafiltered with distilled water (850 Kg/Kg) and concentrated 4× to provide a solution with about 20 g EXAMPLE 1/Kg of solution. This solution was diafiltered with 1% sodium acetate (pH 5.2±0.5, 930 Kg/Kg of EXAMPLE 1). The permeate solution was monitored for chloride by ion selective electrode until the salt exchange (chloride to acetate) was complete. The retentate was monitored for the removal of HOBt by HPLC until the process was complete. The product solution was diafiltered with 20 ppm acetic acid solution (870 Kg/Kg of EXAMPLE 1). The permeate solution was monitored by conductance for sodium acetate until the sodium acetate removal was complete. The retentate was monitored by HPLC for the removal of EDU until complete. The product solution was concentrated to about 80 g EXAMPLE 1/Kg of solution, drained to a container and washed twice with distilled water (4-5 Kg/Kg EXAMPLE 1). The rinses are combined with the product solution. The yield of AcXGVI*TNIRPNHCH2CH3 was about 90-97%.
EXAMPLE 3
The product solution of EXAMPLE 2 (1 Kg, about 42 g AcXGVI*TNIRPNHCH2CH3/Kg solution) was double filtered (0.45 and 0.2 μm filters in series) into a reactor. A distilled water (0.5 Kg) rinse of the filters, acetic acid (0.04 Kg, 0.6-0.7 mole equivalents) and isopropanol (25 Kg/Kg AcXGVI*TNIRPNHCH2CH3.CH3CO2H) are then added to the solution. The solution was distilled under vacuum at 50° C. to approximately 15 L. Additional isoproanol (30 Kg/Kg AcXGVI*TNIRPNHCH2CH3 and 14 Kg/Kg AcXGVI*TNIRPNHCH2CH3) was added, and the distillation was repeated twice. The concentration of water was monitored by Karl Fischer until a ratio of AcXGVI*TNIRPNHCH2CH3(Kg)/water(L)/isopropanol(L) of 1:4:10 was obtained. The solution was warmed to 40° C., treated with isopropanol (4 Kg/Kg AcXGVI*TNIRPNHCH2CH3) to provide a ratio of AcXGVI*TNIRPNHCH2CH3(Kg)/water(L)/isopropanol(L) of 1:4:15. Filtered isopropyl acetate (16 Kg/Kg AcXGVI*TNIRPNHCH2CH3) was added, and the mixture was cooled to 25° C. Additional filtered isopropyl acetate (39 Kg/Kg AcXGVI*TNIRPNHCH2CH3) was added at a rate of 6-9 Kg/h), and the mixture was stirred for 3 hours and filtered. The filtrate was washed with a mixture of isopropanol (3 Kg/Kg AcXGVI*TNIRPNHCH2CH3) and isopropyl acetate (14 Kg/Kg AcXGVI*TNIRPNHCH2CH3). The solids were dried under vacuum at 45° C. for 12 hours, de-lumped with a mortar and pestle and screened through Nos. 10 and 18 sieves. The solids may be hydrated by transferral to a dryer containing a pan of water. The dryer was held at 40° C. for 8-24 hours under vacuum and further dried under vacuum at 45° C. regardless of the optional moisture treatment. The drying was monitored by GC for the removal of isopropanol and isopropyl acetate until complete. The yield of AcXGVI*TNIRPNHCH2CH3.CH3CO2H was 86-94%.
A sample of AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 for powder diffraction analysis was applied as a thin layer, with no prior grinding, to the analysis well of a Scintag×2 Diffraction Pattern System having the following parameters: x-ray source: Cu-Kα; range: 2.00°-40.00° 2θ; scan rate: 1.00 degree per minute; step size: 0.02°; temperature: about 25° C.; wavelength: 1.54178 Å (Cu-Kα).
It is meant to be understood that peak heights may vary and will be dependent on variables such as the temperature, size of crystal size or morphology, sample preparation, or sample height in the analysis well of the Scintag×2 Diffraction Pattern System.
It is also meant to be understood that peak positions may vary when measured with different radiation sources. For example, Cu-Kα1, Mo-Kα, Co-Kα and Fe-Kα radiation, having wavelengths of 1.54060 Å, 0.7107 Å, 1.7902 Å and 1.9373 Å, respectively, may provide peak positions that differ from those measured with Cu-Kα radiation.
The term “about” preceding a series of peak positions is meant to include all of the peak positions of the group which it precedes.
The term “about” preceding a series of peak positions means that all of the peaks of the group which it precedes are reported in terms of angular positions with a variability of ±0.1°.
For example, the phrase about 2.6, 4.7, 5.2, 5.5, 7.2, 8.9, 11.6, 13.6 or 14.4 means about 2.6, about 4.7, about 5.2, about 5.5, about 7.2, about 8.9, about 11.6, about 13.6 or about 14.4 or 2.6±0.1°, 4.7±0.1°, 5.2±0.1°, 5.5±0.1°, 7.2±0.1°, 8.9±0.1°, 11.6±0.1°, 13.6±0.1°or 14.4±0.1°.
The foregoing is meant to be illustrative of the invention and not intended to limit it to the disclosed embodiments. Variations and changes obvious to one skilled in the art are intended to be within the scope and nature of the invention as defined in the claims.

Claims (3)

1. AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 characterized, when measured at about 25° C. with Cu—Kα radiation, by a powder diffraction pattern with peaks having respective 2θ values of about 2.6, 4.7, 5.2, 5.5, 7.2, 8.9, 11.6, 13.6, and 14.4.
2. AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 having substantial crystalline purity and characterized, when measured at about 25° C. with Cu—Kα radiation, by a powder diffraction pattern with peaks having respective 2θ values of about 2.6, 4.7, 5.2, 5.5, 7.2, 8.9, 11.6, 13.6, and 14.4.
3. AcXGVI*TNIRPNHCH2CH3.CH3CO2H Crystalline Form 1 having substantial crystalline purity and substantial chemical purity and characterized, when measured at about 25° C. with Cu—Kα radiation, by a powder diffraction pattern with peaks having respective 2θ values of about 2.6, 4.7, 5.2, 5.5, 7.2, 8.9, 11.6, 13.6, and 14.4.
US11/615,234 2005-12-29 2006-12-22 Crystalline form of a drug Expired - Fee Related US7727953B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/615,234 US7727953B2 (en) 2005-12-29 2006-12-22 Crystalline form of a drug

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US75474305P 2005-12-29 2005-12-29
US11/615,234 US7727953B2 (en) 2005-12-29 2006-12-22 Crystalline form of a drug

Publications (2)

Publication Number Publication Date
US20070185034A1 US20070185034A1 (en) 2007-08-09
US7727953B2 true US7727953B2 (en) 2010-06-01

Family

ID=38334793

Family Applications (1)

Application Number Title Priority Date Filing Date
US11/615,234 Expired - Fee Related US7727953B2 (en) 2005-12-29 2006-12-22 Crystalline form of a drug

Country Status (1)

Country Link
US (1) US7727953B2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100222358A1 (en) * 2006-02-24 2010-09-02 Abbott Laboratories Octahydro-pyrrolo[3,4-b]pyrrole derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6716963B1 (en) 1998-05-22 2004-04-06 Abbott Laboratories Peptide antiangiogenic drugs
US6774211B1 (en) 1998-05-22 2004-08-10 Abbott Laboratories Peptide antiangiogenic drugs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6716963B1 (en) 1998-05-22 2004-04-06 Abbott Laboratories Peptide antiangiogenic drugs
US6774211B1 (en) 1998-05-22 2004-08-10 Abbott Laboratories Peptide antiangiogenic drugs

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Concise Encyclopedia of Chemistry (1993), Walter de Gruyter, Berlin-New York. *
Haleblian et al. Journal of Pharmaceutical Sience, Aug. 1969, vol. 58, No. 8, pp. 911-929. *
Polymorphism in Pharmaceutical Solids, edited by Brittain, 1999, Macel Dekker Inc., pp. 178-179, 185 and 219. *
Rouhi, A.M., Chemical & Engineering New, Feb. 24, 2004, pp. 32-35. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100222358A1 (en) * 2006-02-24 2010-09-02 Abbott Laboratories Octahydro-pyrrolo[3,4-b]pyrrole derivatives
US8399468B2 (en) * 2006-02-24 2013-03-19 Abbott Laboratories Octahydro-pyrrolo[3,4-B]pyrrole derivatives

Also Published As

Publication number Publication date
US20070185034A1 (en) 2007-08-09

Similar Documents

Publication Publication Date Title
RU2603345C2 (en) High purity cyclopeptide compound as well as preparation method and use thereof
KR100408909B1 (en) Novel peptide derivatives
US20240400608A1 (en) Synthesis of bicycle toxin conjugates, and intermediates thereof
WO1994019334A1 (en) Pf1022 derivative, cyclic depsipeptide
JPH01125398A (en) Amino acid derivative and its production
TW200927144A (en) A crystalline synthetic intermediate for preparation of a DPP-IV inhibitor and method of purification thereof
JP2001504453A (en) Glycoconjugates from modified camptothecin derivatives (20-O-linked)
US7727953B2 (en) Crystalline form of a drug
ZA200109944B (en) A substantially crystalline form of melagatran.
CN101077885A (en) New antitumoral compounds
DE60010711T2 (en) AMIDO SPIROPIPERIDINE PROMOTES THE RELEASE OF GROWTH HORMONES
RU2356908C2 (en) Novel antitumor compounds
JP6608442B2 (en) Epoxy ketone compounds used for enzyme inhibition
KR20210087493A (en) Polymorphic Forms of Substituted-quinoxaline-Type Bridged-Piperidine Compounds
US20060063825A1 (en) Crystalline form of a drug
DE3850818T2 (en) Fluorine-containing renin inhibitors.
WO2006034094A1 (en) Crystalline form 1 of atrasentan hxdrochloride
JP2000505053A (en) Novel amine derivatives of epipodophyllotoxin 2 ", 3" -dideoxyglycoside, their preparation, and their use as pharmaceuticals and anticancer therapeutics
JP5462493B2 (en) Cyclic depsipeptide
JP4615712B2 (en) 5-Imino-13-deoxyanthracycline derivatives, their use and methods for their preparation
US20130096275A1 (en) Vancomycin b hydrochloride crystalline form 1
US7745448B2 (en) Crystalline N-(4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl)-N′-(2-fluoro-5-(trifluoromethyl)phenyl)urea ethanolate
JP7759380B2 (en) Salt and crystalline forms of sulfonylurea ring-substituted compounds
CN109456311B (en) 3R-indolylmethyl-6R-aromatic amino acid modified piperazine-2, 5-diketone and synthesis, activity and application thereof
KR20110114690A (en) 4-Methylhexano kahalad F compound

Legal Events

Date Code Title Description
AS Assignment

Owner name: ABBOTT LABORATORIES,ILLINOIS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TOLLE, JOHN C.;SHEIKH, AHMAD Y;SIGNING DATES FROM 20070413 TO 20070416;REEL/FRAME:019176/0584

Owner name: ABBOTT LABORATORIES, ILLINOIS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TOLLE, JOHN C.;SHEIKH, AHMAD Y;REEL/FRAME:019176/0584;SIGNING DATES FROM 20070413 TO 20070416

STCF Information on status: patent grant

Free format text: PATENTED CASE

AS Assignment

Owner name: ABBVIE INC., ILLINOIS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ABBOTT LABORATORIES;REEL/FRAME:030231/0808

Effective date: 20120801

FPAY Fee payment

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552)

Year of fee payment: 8

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20220601